In the early 1980's, there was considerable interest in the development of monoclonal antibodies (Mabs) for use as anti-cancer agents. In some cases, these were designed to be “magic bullets” delivering, by way of conjugation, various cytotoxic compounds (eg toxins) or other substances (eg isotopes and drugs) to the cancerous cells. However, due to a number of reasons including poor specificity, poor penetration (ie with solid tumours) and the induced HAMA (ie human anti-mouse antibody) response, these Mab-based anti-cancer agents were unsuccessful and largely abandoned.
In recent times, there has been renewed interest in Mab-based anti-cancer agents and many of the problems previously experienced have been addressed by genetic engineering techniques (Hudson P. J., “Recombinant-antibody constructs in cancer therapy”, Curr Opin Immunol, 11, pp 548-557 (1999); the disclosure of which is to be considered as incorporated herein by reference). Indeed, there are currently three Mabs (ie the humanised HER2/neuMab marketed under the name Transtuzumab for treatment of HER2/neu positive breast cancer, humanised anti-CD20 Mab known as Rituxan for treatment of Non-Hodgkin lymphoma, and C225 which is an anti-EGFR Mab) which are either being used or are in clinical trials. These antibodies do not act primarily as cytotoxic antibodies nor by Fc mediated inflammatory responses, but rather bind antigen leading to interference in cell signaling and apoptosis. For example, in the case of the HER2/neu Mab, the antibody prevents or “blocks” the binding of a growth factor resulting in the death of HER2/neu positive breast cancer cells.
There is a clear need for more anti-cancer agents to complement existing treatments of cancers. By immunising rats with or an antigenic portion of a Cripto-1 protein (Montuori N, et al. “isolation and characterisation of the CRIPTO autosomal gene and its X-linked related sequence”, Am J Hum Genet, 49(3), pp 555-565 (1991)) known to be expressed in certain cancer cells, or a fusion protein of a Pim-1 protein (Friedmann M, et al. “Characterisation of the proto-oncogene pim-1: kinase activity and substrate recognition sequence”, Arch Biochem Biophys, 298 (2), pp 594-601 (1992), or a colon cancer cell lysate, the present applicant has produced monoclonal antibodies which have been found, surprisingly, to inhibit growth of various cancer cell lines.